• Nuclear Pirin promotes HCC by acting as a key inflammation-facilitating factor
• Effects of Pirin-like proteins on PAT biosynthesis and stress resilience in postharvest apple pathogen Penicillium expansum
• Corrigendum to "Pirin is a nuclear redox-sensitive modulator of autophagy-dependent ferroptosis" [Biochem. Biophys. Res. Commun. 536 (2021) 100-106]
• The m6A hypermethylation-induced PIR overexpression regulates H3K4me3 and promotes tumorigenesis of uveal melanoma
• Inhibition of mast cell activation by Jaranol-targeted Pirin ameliorates allergic responses in mouse allergic rhinitis
• Genome-Wide Identification and Characterization of the Pirin Gene Family in Nicotiana benthamiana
• Mechanistic insights into Rho/MRTF inhibition-induced apoptotic events and prevention of drug resistance in melanoma: implications for the involvement of pirin
• A plasmid-chromosome crosstalk in multidrug resistant enterobacteria

Definition: *Pirin* is a highly conserved nuclear protein belonging to the cupin superfamily. It functions as a transcriptional co-regulator, interacting with key factors such as NF-κB, and is implicated in oxidative stress responses, inflammation, and cancer progression.

• Gene: *PIR* (located on chromosome 1q21.3 in humans).
• Structure: Contains a cupin-like β-barrel domain capable of binding metal ions (e.g., iron, zinc).
• Localization: Mainly nuclear, but cytoplasmic presence observed in some cancers.

• Oncogenic potential: Pirin is overexpressed in several cancers including melanoma, lung cancer, breast cancer, and gliomas.
• Promotes EMT and metastasis: Through modulation of NF-κB and other pathways.
• Possible biomarker: Elevated PIR expression correlates with poor prognosis in multiple tumor types.
• Potential therapeutic target: Inhibition of pirin-NF-κB interaction is under investigation.

• Pirin is induced by oxidative stress and inflammatory cytokines (e.g., TNF-α, IL-1β).
• Acts as a redox-sensitive transcriptional regulator—key in linking inflammation to tumorigenesis.

• Pirin modulates IL-8 and matrix metalloproteinase (MMP) expression in cancer cells.
• Studies show iron-bound pirin (holo-pirin) promotes pro-inflammatory transcriptional programs more than its iron-free form.
• Possible link to neuroinflammation via glial activation and redox imbalance.

• Cancer biology: Pirin may serve as a prognostic biomarker and therapeutic target in aggressive cancers.
• Redox-inflammation axis: Represents a molecular hub for oxidative stress and chronic inflammation.
• Neurology: Under investigation for its role in neuroinflammation and neurodegeneration.

• Wendler WM, et al. (2006). Pirin, a novel nuclear protein, interacts with NF-κB p65 and modulates its transcriptional activity. *J Biol Chem*.
• Liu Y, et al. (2019). Pirin regulates epithelial–mesenchymal transition in lung cancer via NF-κB pathway. *Oncol Rep*.
• De Simone G, et al. (2013). Pirin as a potential target in cancer therapy. *FEBS Lett*.

In a Experimental study using in vitro cell lines and in vivo mouse models, supplemented with transcriptomics, western blotting, qRT-PCR, immunofluorescence, and immunohistochemistry. Ma et al. from the Xiamen University, Xiamen, China. published in the *Gut Journal*, online ahead of print: June 27, 2025. to investigate Pirin (PIR) as a redox-sensitive transcriptional regulator and pro-inflammatory factor in hepatocellular carcinoma (HCC) pathogenesis ¹⁾.

1. PIR undergoes redox-mediated nuclear translocation, enhancing inflammatory transcription via RELA. 2. This creates a positive feedback loop that increases proinflammatory cytokines and promotes HCC progression. 3. PIR inhibition (genetic/pharmacological) or treatment with N-acetyl cysteine attenuates tumor growth and inflammation in mouse models. 4. Liver parenchymal cells demonstrate autocrine cytokine production under PIR influence, directly contributing to malignancy.

- Strengths:

1. Mechanistically rich; integrates redox biology, transcriptional regulation, and tumor immunopathology.
2. Robust experimental design across molecular, cellular, and organismal levels.
3. Data support PIR as a central inflammatory amplifier with translational potential.

- Limitations:

1. The study remains preclinical — lacking validation in human tissue cohorts or prospective clinical samples.
2. While inflammation is implicated, direct links to immune cell behavior or microenvironmental shifts remain underexplored.
3. Therapeutic interventions like NAC, although promising, need careful pharmacokinetic validation for clinical extrapolation.
4. The oncogenic specificity of PIR needs contrast with other tumor models—i.e., is this HCC-specific or broadly pro-tumorigenic?

- Score: 8/10 — a conceptually innovative, well-executed mechanistic study with significant translational implications, pending clinical correlation.

While not directly neurosurgical, this study reinforces the broader principle that redox-sensitive transcriptional regulators (like PIR) may be pro-inflammatory oncogenic drivers—a paradigm potentially relevant in gliomas or other CNS tumors influenced by inflammation.

Pirin’s nuclear activity under oxidative stress orchestrates a self-sustaining inflammatory loop that drives HCC, suggesting a novel antioxidant-modifiable target for tumor suppression.

Nuclear Pirin promotes HCC by acting as a key inflammation-facilitating factor. Ma H, et al. *Gut.* Published online June 27, 2025. doi:10.1136/gutjnl‑2024‑334087. Corresponding authors: Qinxi Li (liqinxi@xmu.edu.cn), Weiling He (wlhe@xah.xmu.edu.cn)